Prolotherapy (and related) Research: Summary and Status Updated From Talk at AAOM 29th Annual Conference April 18-21 2012 K. Dean Reeves, M.D. Clinical Associate Professor University of Kansas
Sections of Talk • Definitions
Prolo or Prolo-Related Treatments (Focus on Red) (Can we be reimbursed fairly? Nomenclature for Research) BRI : Biologic Repair Injection Injection of biologics to repair connective tissue. Injection to repair connective tissue (Lig/Tend/Cart) (Not including biologics) Prolotherapy (Prolo) Subcutaneous injection to restore function in pain producing sensory nerves. PSI (Perineural Subcutaneous Injection) PDI (Perineural Deep Injection) Also called hydrodissection Deeper nerve stretch, typically with ultrasound guidance. Caudal Dex: Caudal Dextrose Injection Caudal dextrose Injection T-Dex/T-VitD : Topical Dextrose or Vitamin D Application of lotion to restore normal function in pain producing sensory nerves.
Def: Biologic and Biologic Repair Injection (BRI) • Biologic: A preparation that is synthesized from living organisms or their products and used medically as a diagnostic, preventive, or therapeutic agent. www.thefreedictionary/biologic • B.R.I.: Injection of biologics to repair connective tissue. • Mechanism proposed is by stimulation of a repair cascade • Various methods are utilized. IE: Whole blood, PRP, stem cells. • Emphasis is on direct regenerative/proliferative effects on connective tissue.
Def: Prolo and PSI • Prolotherapy: Injection to repair connective tissue (Not including biologics) • Mechanism proposed is by stimulation of a repair cascade by as an effect of needling or solution. • Various injectants are utilized. • Emphasis is on direct regenerative/proliferative effects on connective tissue. • PSI (Perineural Subcutaneous Injection):Subcutaneous or non guided near nerve injection to restore function to peptidergic sensory nerves. • Mechanism proposed is by downregulation of the TRPV1 receptor, but this has not been determined) • Injectant is dextrose currently but other solutions may be utilized as discoveries occur) • Emphasis is on a direct, primarily immediate, effect on peptidergic nerves.
Def: PDI (Perineural Deep Injection) (Hydrodissection ) • Stretching a deeper sensory or combined sensory/ motor nerve under guidance. • Mechanism proposed is by untethering/restoration of normal motion to a peripheral nerve. • If dextrose is utilized (Dextrose hydrodissection), an additional mechanism is restoration of nerve function by a direct effect of dextrose. • If lidocaine is utilized (Lidocaine hydrodissection), an additional mechanism is nerve block • If steroid is utilized (Steroid hydrodissection), an additional mechanism is a local effect on arachadonic acid inflammation pathway.
Def: Other • Caudal Dextrose Injection: Guided or unguided injection of dextrose into the caudal epidural space. • Mechanism is proposed to be partly a hydrodissection effect and a direct nerve effect of dextrose, but this has not been determined. • Transdermal Dextrose: Application of dextrose to the skin for therapeutic purposes. • Mechanism is proposed to be via downregulation of the TRPV1 receptor, but this has not been determined. • Penetrating agents or other methods of delivery or solutions may be utilized. IE: Ultrasound Delivery of Transdermal Dextrose/Vitamin D
Sections of Talk • Levels of Evidence
U.S. Preventative Service Task Force Basic Classification of Evidence • Level I: Well designed RCT (s) with clinical and statistically significant evidence. • Level II: Well designed: II-1 Controlled trials without randomization. Controlled treatment comparison studies. II-2 Cohort (delayed Rx) studies from more than one center. II-3 Uncontrolled trial with dramatic result. Uncontrolled trial with blindable objective outcome measure. Level III. Substantially flawed RCTs or other controlled studies. Single well designed cohort or case control study.
Sections of Talk • Taking Over the World (Evidence that forces change.)
Study Characteristics That Force Change • Change will be forced if TWO studies are published in Pub Med journals that are good size, show both clinical and statistically significant benefit, have adequate follow-up, good data capture, and use accepted tools, PARTICULARLY if they use simple, inexpensive and minimally invasive methods which are practical for a primary care practitioner.
Sections of Talk • Where are we on the evidence with dextrose? (Using the grading we mentioned)
Steroid vs Dextrose SI Injection • Kim WM, Lee HG, Won Jeong C, Kim CM, Yoon MH. A randomized controlled trial of intra-articular prolotherapy versus steroid injection for sacroiliac joint pain. J Altern Complement Med Dec 2010, 16(12) p1285-90.
50% Imp with SI Inj with 2.5 ml L-bupiv Pain > 3 mo below PSIS or + Gaenslen’s or Patrick maneu. 50 Randomized 26 24 Fluoro Guidance 25% Dexin .125 L-bupiv @ 0, 2 & 4 weeks PRN 10% pain 40 mg Triam in .125 L-bupiv @ 0, 2 & 4 weeks PRN 10% Pain 1 Lost to Fup 1 Dropout (pain) 25 23 Followup to 15 months for Pain and Oswestry Disability Index (ODI)
% with ≥ 50% Pain Relief P < .001
Osgood-Schlatter Disease • Topol GA, Podesta LA, Reeves KD, Raya MF, Fullerton BD, Yeh H. Hyperosmolar Dextrose Injection for Recalcitrant Osgood-Schlatter Disease. Pediatrics 2011;128(5):e1121-e1128.
66 Improved With Additional Therapy 2 694 Screened OSD Criteria Met 54 10 Refused Enrollment Randomized 19 17 Dextrose Injection monthly for 3 months Usual Care for 3 months Lidocaine injection monthly for 3 months 17 19 18 3 month data collection, unblinding, and optional dextrose injection for 1 year 1 year data
3 1 4 2 Fragmented Tibial Tuberosity Tibia Above Tuberosity Tibia Below Tuberosity
N P P S S C O R E
Dex (n=21) Usual Only (n=14) Usual-Dex (n=8)
Review by Essential Evidence Plus “POEMs” = "Patient-Oriented Evidence that Matters”. This is from January 7, 2012. Avg 24/3000 articles
Knee OA 2012 (Dextrose vs Exercise Crossover ) • Dumais R, Benoit C, Dumais A, Babin L, Bordage R, de Arcos C, Allard J, Bélanger M. Effect of Regenerative Injection Therapy on Function and Pain in Patients with Knee Osteoarthritis: A Randomized Crossover Study. Pain Med. 2012 Jul 3. doi: 10.1111/j.1526-4637.2012.01422.x. [Epub ahead of print]
OA Knee Diagnosis, Chronicity, No Prior Surgery = #45/60 screened 21 24 Dextrose 25% 5 ml IA, 15% Col. Lig @ 0,4, 8, 12 weeks† Home-Based Exercise Program* Without Injection Home based Exercise program Without Further Injection Dextrose 25% 5 ml IA, 15% Col. Lig @ 20, 24, 28, 32 weeeks. Follow-up every 4 weeks in BOTH groups. No NSAIDs. WOMAC 3.1, Brief Pain Inventory, Wong-Baker Faces, NRS, Timed Up and Go Test. Measurers blinded. Focus on Changes from 0 to 16 weeks and 20 to 36 weeks
Data Collection Weaknesses • Only 18/21 in 1st period treatment analyzed as 2 “completely rehabilitated” and 2 no better and did not return. Could not do physical testing so data not included. • Only 18/24 in 2nd period analyzed at 3 refused participation after randomization and 2 lost to follow-up. • These reflect deficiencies in follow method and in candidacy determination (IE willingness to participate even if not assigned to active treatment immediately. These were not likely to affect outcome. • Note two failures of injection , one “no better” and one”pain with injection”. Each quit before final data .
Finger OA 2000 • Reeves KD, Hassanein K: Randomized prospective placebo-controlled double-blind study of dextrose prolotherapy for osteoarthritic thumbs and fingers (DIP, PIP and trapeziometacarpal Joints) : Evidence of clinical efficacy. Jnl Alt Compl Med 2000;6(4):311-320.
Kelgreen Criteria for hand OA met plus pain > 3 months 14 13 Dex10%/ .075 Lido injection at 0, 2 and 4 months .075 Lidocaine inj. at 0, 2 and 4 months. 2 Lost for medical reasons (progressive CHF and severe depression 11 14 6 month data, then open label Dextrose 10% PRN 3 3 dropped out (1 much better and 2 not improved) 11 11 1 year data collection on 22 patients. Intention to treat.
% Impr. Movement Pain After 3 Injections (P = .027)
Impr. Finger Flexion in Degrees Dextrose +8 Lidocaine -8.7 (P = .003)
Extensor Tendinosis • Scarpone M, Rabago DP, Zgierska A, Arbogast G, Snell E: The efficacy of prolotherapy for lateral epicondylosis: a pilot study. Clin J Sport Med 2008;18(3):248-5
26 met criteria for Criteria of 6 months pain, failure of rest, P.T., NSAIDs and two Steroid injections. NSAIDs discouraged. No peppering 10 10 10.7% Dex/14.7% NaMorr Three 0.5 ml portions @ 0, 4 & 8 wks Normal Saline Same Volume @ 0, 4 & 8 wks 10 (One moved after 16 weeks) 9 Grip strength by dynamometer, extension strength by BTE, and pain score NRS at 8, 16 and 52 weeks
Extensor Strength From 0 to 4 Months (P < .01)
Knee OA Intraarticular RCT 2000 • Reeves KD, Hassanein K. Randomized Prospective Double-Blind Placebo-Controlled Study of Dextrose Prolotherapy for Knee Osteoarthritis With or Without ACL laxity. Alt TherHlth Med 2000;6(2):68-80
77 Patients Enrolled 39 38 .075% Lido in BW/.9BA 10% Dex/.075% Lido/.9BA 3 unrelated medical dropouts and 1 efficacy dropout to 1 year 2 unrelated medical dropouts and 3 efficacy dropouts to 1 year. 53 Knees 58 Knees 34 Subjects 34 Subjects 0, 2 and 4 month injections. ROM, pain data at 6 months. Then open label dextrose Q 2-3 months PRN. ROM, Pain, blinded X-Ray data at 1 year
Group Similarities in OA Knee Study • Groups were similar, however, 25 knees were Stage IV in the dextrose group and only 15 in the Lid/BA group. • Buckling episodes in past 2 months: Estimated 7.8 in dextrose group and 1.0 in the lidocaine/benzyl alcohol group.